The invention relates to novel 2-substituted 3-hydroxythiazolo[2,3-b]benzothiazolium salts, 2-substituted thiazolo-[2,3-b]benzothiazol-3(2H)-one mesoionic didehydro derivatives, 2-substituted thiazolo[2', 3'-2,3]-thiazolo[5,4-b]pyridin-3(2H)-one mesoionic didehydro derivatives and related compounds, and their use as modulators of the immune response.
In recent years, the rapid upsurge in immunological research has brought about a greater appreciation and understanding of the complexities of the immune response. While the traditional overall view of the immune system remains, new discoveries have radically changed some thinking about the details of the system. Thus, the immune system is still divided into humoral immunity, populated with B cells and responsible for antibody formation, and cell-mediated immunity, populated with T cells and responsible for the rejection or organ transplants or skin grafts, as well as the defense mechanism against various foreign biological matter and endogenous neoplastic growths.
It is only in the last decade or so, however, that the concept has been accepted that different cell populations interact in the induction and expression of both humoral and cell-mediated immunity. Thus, subpopulations of B cells and T cells have been described, such as for example "suppressor" and "helper" T cells. In a number of animal models, it has been postulated that the helper T cells act in the induction of a complete antibody response to many antigens, whereas T suppressor cells are capable of preventing or terminating such responses. It is now believed that positive and negative cellular interactions control the ultimate degree of immune response. So, it is believed that any given immune response is regulated, and that the degree and mode of regulation may ultimately explain the various reactions, diseases, and disorders which are the manifestations of the operation of the organism's immune system.
The T cell subpopulations of suppressor and helper T cells have been implicated in a number of immune response manifestations. Thus, the loss of suppressor T cells is now believed to be a major factor in such autoimmune connective tissue disease as systemic lupus erythematosus. Moreover, in the latter case, as well as in probable impaired immune system responses such as rheumatoid arthritis, it is believed that the helper T cells exacerbate the condition.
Also, the theory has been advanced that T suppressor cell hypofunctioning, resulting in inadequate T-B cell cooperation in the immune response, with continuous B cell stimulation and subsequent antibody production may be the cause of the production of antigen-antibody complexes which are the causative agents of renal and inflammatory processes in arthritis and autoimmune diseases.
Thus, it is now apparent that a number of lymphopoietic disorders are undoubtedly associated with abnormalities of T cell and especially suppressor cell function. The loss of suppressor function is at least an early event in certain immune response diseases and is a disease-perpetuating mechanism in others. The loss of suppressor function probably leads to excessive lymphoid cell proliferation and may significantly contribute to lymphoproliferative disorders. The conditions created thereby may be exacerbated by helper T cells.
The role of immunomodulatory agents in the treatment of immune diseases and disorders, as well as in the attempt to prolong the life of organ transplants and skin grafts, has been to suppress the immune response, especially of cell-mediated immunity. By suppressing the cell-mediated immune response, it is possible to delay and possibly prevent the host organism from rejecting a skin graft or organ transplant, or the graft from immunologically rejecting the host (graft vs. host reaction). Similarly, enhancing or reinstituting suppressor function by immunomodulator therapy is a beneficial course of treatment for antoimmune and probable antoimmune diseases and disorders. However, the current immunosuppressive agents have the serious drawback that in effective doses they suppress the entire immune response. Thus, they suppress both the cell-mediated and humoral immunity, with the result that the patient is left without immunity to infections which he could otherwise readily overcome without medical aid. Thus, the hitherto known immunosuppressive agents are not selective in their action.
The compounds of the present invention, however, are highly selective immunomodulatory agents which are especially indicated in the treatment of various skin graft and organ transplant reactions, and immune system diseases and disorders such as systemic lupus erythematosus and rheumatoid arthritis, whose etiology is probably suppressor T cell dysfunction.